Carbonic anhydrases (CAs; also known as carbonate dehydratases EC 4.2.1.1) are ubiquitous metalloenzymes present in prokaryotes and eukaryotes that are encoded by four evolutionarily unrelated gene families. CAs catalyse a simple physiological reaction the conversion of CO2 to the bicarbonate ion and protons. The active site of most CAs contains a zinc ion (Zn2+), which is essential for catalysis. The CA reaction is involved in many physiological and pathological processes, including respiration and transport of CO2 and bicarbonate between metabolizing tissues and lungs; pH and CO2 homeostasis; electrolyte secretion in various tissues and organs; biosynthetic reactions (such as gluconeogenesis, lipogenesis and ureagenesis); bone resorption; calcification; and tumorigenicity.
Many of the CA isozymes involved in these processes are important therapeutic targets with the potential to be inhibited to treat a range of disorders including oedema, glaucoma, obesity, cancer, epilepsy and osteoporosis. Two main classes of CA inhibitors (CAIs) are known: the metal-complexing anions and the unsubstituted sulphonamides and their bioisosteres. CAIs include the classical inhibitors acetazolamide, methazolamide, ethoxzolamide, sulthiame and dichlorophenamide.
The reduced compounds (thiols) are less bulky and show excellent CA inhibitory activity (in the low nanomolar range) compared with the corresponding sterically hindered disulphides, which have difficulty entering the limited space of the enzyme active site and also with low bioavailability as well as poor pharmacokinetics with very common side effects such as numbness in toes, taste, ataxia, paraesthesia of face and limbs and blurred vision.
Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of carbonic anhydrase enzyme activity and its associated complications progression.